In the adaptive immune response, foreign antigens are recognized by receptor molecules on B lymphocytes (e.g., immunoglobulins) and T lymphocytes (e.g., T cell receptors or TCRs). While pathogens in the blood and extracellular space are recognized by antibodies in the course of humoral immune response, destruction of pathogens inside cells is mediated in the course of cellular immune response by T cells.
T cells recognize and attack antigens presented to them in the context of a Major Histocompatibility Complex (MHC) on the cell surface. The antigen recognition is mediated by TCRs expressed on the surface of the T cells. Two main classes of T cells serve this function: cytotoxic T cells, which express a cell-surface protein CD8, and helper T cells, which express a cell-surface protein CD4. Cytotoxic T cells activate signaling cascades that result in direct destruction of the cell presenting the antigen (in the context of MHC I), while helper T cells differentiate into several classes, and their activation (primed by recognition of antigen presented in the context of MHC II) results in macrophage-mediated pathogen destruction and stimulation of antibody production by B cells.
Because of their antigen specificity, antibodies are presently widely studied for their therapeutic potential against numerous human disorders. To generate antibodies capable of neutralizing human targets, while simultaneously avoiding activation of immune responses against such antibodies, scientists have concentrated their efforts on producing human or humanized immunoglobulins. One way of producing humanized antibodies in vivo is by using VELOCIMMUNE® mouse, a humanized mouse comprising (1) unrearranged human immunoglobulin V, D, and J segment repertoire operably linked to each other and a mouse constant region at the endogenous mouse immunoglobulin heavy chain locus and (2) unrearranged human Vκ and Jκ segment repertoire operably linked to each other and a mouse constant κ region at the endogenous mouse immunoglobulin κ light chain locus. As such, VELOCIMMUNE® mice provide a rich source of highly diverse rearranged antibody variable domains for use in engineering human antibodies.
Similar to an antibody, a T cell receptor comprises a variable region, encoded by unrearranged loci (α and β loci, or δ and γ loci) comprising V(D)J variable region segments, and this variable region confers upon the T cell its antigen binding specificity. Also similar to an antibody, the TCR specificity for its antigen can be utilized for development of novel therapeutics. Thus, there is a need in the art for non-human animals (e.g., rodents, e.g., rats or mice) that comprise unrearranged human T cell variable region gene segments capable of rearranging to form genes that encode human T cell receptor variable domains, including domains that are cognate with one another, and including domains that specifically bind an antigen of interest. There is also a need for non-human animals that comprise T cell variable region loci that comprise conservative humanizations, including non-human animals that comprise unrearranged human gene segments that can rearrange to form T cell receptor variable region genes that are linked to non-human (endogenous) T cell receptor constant gene sequences. There remains a need for non-human animals that are capable of generating a diverse repertoire of human T cell receptor variable sequences. There is a need for non-human animals that are capable of rearranging most or all functional T cell receptor variable region segments, in response to an antigen of interest, to form T cell receptor polypeptides that comprise fully human variable domains.